Interferon alpha (IFN-alpha) therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the antiviral and antitumor activity of IFN alpha are not clear. Primary mouse and rat hepatocytes respond poorly to IFN alpha stimulation. The aim of this project is to examine the IFN alpha signal pathway in primary human hepatocytes. We demonstrate that primary human hepatocytes respond very well to IFN alpha stimulation as demonstrated by activation of multiple signal transducer and activator transcription factors (STAT) 1, 2, 3 5 and multiple genes. IFN alpha upregulates more than 50 genes by over 2 fold and downregulates more than 20 genes by 50%. The upregulated-genes include antiviral genes (MxA, OAS, PKR), tumor suppressors/proapoptotic genes (IRF-1, Mac-2BP, I01F6, STAT1, calpain, 9-27, etc), and the aflatoxin B1 aldehyde reductase gene. The downregulated-genes include c-myc and HGF receptor (c-Met). Downregulation of c-Met is due to IFN-alpha suppression of the c-Met promoter through downregulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation.